Dietary polyphenols and the risk of metabolic syndrome: a systematic review and meta-analysis

Background Accumulating evidence has suggested that dietary polyphenols may be protective against metabolic syndrome (MetS); however, the available evidence is contradictory. The aim of this meta-analysis was to assess the association between dietary intake of polyphenols and the odds of MetS. Methods The PubMed and Scopus databases were systematically searched to obtain eligible studies. The risk of MetS for the highest versus the lowest intakes of total, subclasses and individual polyphenols were examined by pooling odds ratios (OR) and 95% confidence intervals (95%CI) using the random effects model. Results A total of 14 studies (6 cohort and 8 cross-sectional studies) involving a total of 50,366 participants with 10,879 cases of MetS were included. When various polyphenol compounds were pooled, they were significantly related to a 22% decreased odds of MetS (([5 studies]; OR: 0.78; 95%CI: 0.72–0.85). Higher intakes of total flavonoids (([9 studies]; OR: 0.78; 95%CI: 0.72–0.85), flavan-3-ols (([2 studies]; OR: 0.64; 95%CI: 0.43–0.94), isoflavones (([3 studies]; OR: 0.84; 95%CI: 0.75–0.93), stilbenes (([4 studies]; OR: 0.86; 95%CI: 0.76–0.97), flavones (([2 studies]; OR: 0.79; 95%CI: 0.71–0.89), and quercetin (([2 studies]; OR: 0.63; 95%CI: 0.43–0.93) were also significantly associated with a decreased risk of MetS. The associations were not modified by the age of the participants. No association was found for total polyphenols, phenolic acids, lignans, anthocyanins, and flavonols. Conclusion The results of this meta-analysis supported that higher polyphenol intake can lower the risk of MetS. Supplementary Information The online version contains supplementary material available at 10.1186/s12902-024-01556-x.


Background
Metabolic syndrome (MetS) is a multifactorial and complex complication featured by a cluster of metabolic aberrations, comprising hypertension, adnominal obesity, impaired glucose metabolism, and dyslipidemia [1,2].The prevalence of MetS is increasing globally and has become a main public health issue, as it dramatically increases the odds of chronic diseases, such as cardiovascular disease (CVD), type 2 diabetes mellitus as well as mortality [3].Thus, recognizing amendable risk factors of MetS is of extreme significance to develop preventive strategies to reduce its related pathologies [4].
Among the leading contributing factors, sedentary lifestyles and unhealthy dietary patterns have been frequently identified to be responsible for the etiology of this disease [5].Evidence has revealed that high-quality diets, including the Mediterranean diet and plant-based diets such as the vegetarian dietary pattern, have protective effects against MetS or could even recover the MetS phenotype [6,7].These diets are rich in plants and their beneficial effects are partly attributed to polyphenols, the most widely distributed secondary metabolites in dietary sources which are available in plant-based food such as nuts, whole grains, vegetables, beverages, fruits, and cocoa products [8,9].Polyphenols are a diverse group of bioactive antioxidants belonging to the four chief classes, including lignans, phenolic acids, flavonoids, and stilbenes [10].Due to the antioxidant, anti-inflammatory, and antihyperglycemic properties as well as their positive impacts on metabolic pathways and gut microbiota [11][12][13], polyphenols have received considerable attention for their potential to exert protective effects against the development of MetS components.Despite promising effects on single compounds of MetS [14], epidemiological studies have yielded inconclusive results for the association between the intakes of total polyphenols and main subclasses and the risk of MetS phenotype.The prospective cohort study by Sohrab et al. on 1265 adults, identified no significant relationship between total polyphenol consumption and other subclasses with MetS [15], while higher intakes of total polyphenols, phenolic acid, and flavonoids were linked to reduced odds of MetS in a Danish cohort [9].The disagreement in the results of the previous studies may be due the differences in study design, sample size, or geographic region.
To the best of our knowledge, no systematic review or meta-analysis has yet focused on the association of polyphenols with MetS by pooling the results of observational studies.However, some systematic reviews and meta-analyses on clinical trials have reported that supplementation with polyphenols could improve some individual components of metabolic syndrome [16,17].A recent systematic review identified that supplementation with flavonoids can significantly modulate several metabolic parameters, such as lipid profile, blood pressure, and blood glucose, while no significant effect was reported on body weight and body mass index [18].In contrast, another systematic review did not find a positive effect for grape polyphenols on the components of MetS [19].Currently, it is not known whether the consumption of polyphenols can play a role in the prevention of MetS.Due to the contradiction in the results of observational studies that investigated the relationship between polyphenols and MetS and the lack of a metaanalysis in this field, the present study aimed to quantify the relationship between total dietary polyphenol intake and their subclasses and the risk of MetS by conducting a meta-analysis.

Methods
The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed to present the results of this meta-analysis [20] (Supplementary Appendix 1).The protocol of the study was registered in PROSPERO (CRD42023451126).

Search strategy
A systematic search in PubMed and Scopus was conducted to obtain pertinent publications published from commencement to July 2023 with the use of the following search strategy: ((((((((((((( AND ((("Metabolic Syndrome"[Mesh]) OR (metabolic syndrome))).No language restriction was considered for the literature search.The full electronic search strategy is presented in Table S1.Additionally, the references of the pertinent publications were manually reviewed to find any unrecognized studies.

Eligibility criteria and study selection
Initially, all retrieved publications were compiled in the EndNote reference manager software (version 7) [21].Two researchers (PR and NG) independently were involved in title/abstract screening and full-text screening of the papers and discrepancies were solved by a discussion with a third reviewer.Studies were included based on the following criteria: (1) studies that assessed the relation of the intakes of various dietary polyphenols (exposure) to MetS (outcome), (2) studies were observational in design (cohort, case-control, cross-sectional), (3) studies that provided risk estimates (relative risk (RR), odds ratio (OR), or hazard ratio (HR) along with 95% confidence intervals (CI); when a publication reported more than one effect size for subgroups (e.g.men and women), all effect sizes were extracted.We extracted risk estimates from the most adjusted models.Review studies, letters, book chapters, animal studies, molecular studies on gene expression, studies with inappropriate exposure/outcome, and studies with unextractable data were all excluded from the analysis.

Data extraction and quality assessment
The following data were gathered from each included article with the use of a standardized extraction sheet.The name of the first author, publication year, gender and age of participants, study design, country, total sample size, number of cases with MetS, criteria used for the definition of MetS, dietary assessment tool, risk estimates (OR, RR, or HR) and 95%CI for the associations, type of polyphenols or their subclasses, and covariates adjusted for in the analyses.In most of the studies included in the meta-analysis, effect sizes were reported for polyphenols and its subclasses, separately.For these studies, we extracted all effect sizes and reported the results for different polyphenols in subgroup analysis.For example, in the study by Hejazi et al. [22], effect sizes were reported separately for total flavonoids, anthocyanins, flavones, isoflavones, and flavonols, resulting in multiple effect sizes in the present meta-analysis.The process of data extraction was independently conducted by two investigators and differences were resolved by a group discussion.The quality of the included studies was scored by the Newcastle-Ottawa Scale (NOS), which ranges from 0 to 9 and scores 0-3, 4-6, and 7-9 are representative of low, moderate, and high quality, respectively [23].

Statistical analysis
ORs with 95%CIs were used as the measure of the association of polyphenols and individual classes with MetS for the highest categories of exposure, compared to the lowest exposure.Meta-analysis was carried out when there were at least 2 effect sizes with a common exposure.Heterogeneity across the publications was measured using the Cochrane Q and I-squared statistics, and heterogeneity was defined as I 2 > 50% and p < 0.05 [24].Because of the anticipated heterogeneity, the random-effects model proposed by DerSimonian and Laird (DL) [25] was applied to pool the effect sizes, since it considers both within-study and between-study variations.Subgroup analysis by study design, polyphenol subclasses, definition of MetS, and dietary assessment tool was conducted only in the case when the heterogeneity was significant with the aim to explore the sources of heterogeneity, and when the number of included studies in the meta-analysis was at least 10.A sensitivity analysis was carried out by exclusion of individual articles from the overall analysis step by step to investigate the stability of findings.Moreover, we carried out a meta-regression analysis to check whether the association of polyphenols consumption with MetS is modified by the age of participants.Publication bias was evaluated by inspecting asymmetry in funnel plots and Egger's test [26].All statistical analyses were done with the use of Stata MP 14.0 (Stata Corp., College Station, TX, USA).

Meta-regression and publication bias
Meta-regression analysis according to the age of participants detected that the relation of various polyphenolic compounds to MetS was not modified by the age (p = 0.25) (Fig. 4).Furthermore, no evidence of publication bias was observed based on the Egger's test (t = − 0.14, p = 0.88) (Fig. 5).

Discussion
This meta-analysis identified that a higher dietary intake of total polyphenols, stilbenes, phenolic acids, and total flavonoids, with some of its subclasses including flavones, quercetin, flavan-3-ols, isoflavones, flavones, and quercetin, is associated with lower risk of MetS.No significant association was revealed for total polyphenols, phenolic acids, lignans or other subclasses of flavonoids (anthocyanins, and flavonols) probably because of the small number of analyzed studies for these groups.
Edible plants and beverages provide generous amounts of polyphenols in the human diet [37].Accumulating evidence from preclinical, clinical, and observational studies suggests that polyphenols might prevent or delay MetS development by improving blood pressure, blood glucose, body weight, and lipid metabolism [14,18,38].Nevertheless, epidemiological studies have reported inconsistent findings for the relation of polyphenols to MetS.The cross-sectional study by Wisnuwardani et al. [39] showed no association between the intake of total polyphenols, polyphenol classes, individual polyphenols and MetS risk in adolescents.In agreement with our meta-analysis, the Framingham Offspring Study demonstrated that a high intake of phytoestrogens, a class of phenolic compounds, is linked to a favorable metabolic cardiovascular risk profile and MetS score in postmenopausal women [40].Plasma phytoestrogen concentrations have been also shown to be negatively associated with MetS risk in the Chinese population [41].However, Kim et al. [42] identified no significant differences in dietary intake of isoflavones, daidzein, and genistein between patients with and without MetS.In contrast, Popiolek-Kalisz el al [43].measured differences in habitual consumption of flavonols between patients with MetS and healthy population and found that the intake of isorhamnetin, total flavonols, quercetin, and kaempferol is significantly lower in MetS patients, and a moderate reverse correlation was detected between total flavonols, kaempferol, quercetin, isorhamnetin and MetS stage.The controversy in the results of the previous studies may be due to differences in main food sources, dietary assessment method, study design, definition of MetS, and genetic background of various studied populations.The present meta-analysis reduced these inconsistencies by increasing the pooled sample size and recognized a significant protection of polyphenols against MetS.This meta-analysis found that the majority of polyphenol compounds were significantly related to decreased odds of MetS, but no association was found for total polyphenols, phenolic acids, lignans, anthocyanins, and flavonols.These differences may be due to the multifaceted nature of MetS, variations in the bioavailability and metabolism of polyphenols, and the complex interactions between different polyphenol compounds and metabolic pathways [44].The complex nature of MetS involves multiple interconnected factors such as obesity, insulin resistance, hypertension, and dyslipidemia [1,2].Different polyphenol compounds have different mechanisms of action and may have varying effects on these components, leading to a lack of uniform association with MetS [45].For example, some polyphenols may have a greater impact on blood glucose levels, while others may be more effective in reducing blood pressure or body weight [44].In addition, these compounds are presented in a wide variety of foods, and the specific foods and amounts consumed by the people may have varied widely, which could have affected the results [9].The observed differences may also be due to the fact that the bioavailability and metabolism of polyphenols are different [46].The protective functions of polyphenol compounds may only become effective through frequent and sustained intake over the long term, as part of a healthy and diversified diet [27].Additionally, the composition of polyphenolrich foods is complex and they may have additive or  synergistic effects, making it challenging to isolate their individual effects on MetS [44].This suggests that the association between polyphenols and MetS may not be universally observed and could vary based on the specific polyphenol compounds and their interactions with the complex metabolic pathways involved in MetS.
Overall, the biological mechanisms of various polyphenols in preventing MetS are multifaceted and involve modulation of metabolic parameters, regulation of gene expression, modulation of gut microbiota, anti-inflammatory effects, improvement of insulin resistance, and antioxidant effects [15,47].Flavonoids can significantly improve several metabolic parameters, such as lipid profile, blood pressure, and blood glucose levels, which are individual components of MetS [18].Polyphenols have been found to exert regulatory effects on gene expression in metabolic pathways, including glucose and lipid metabolism, and energy expenditure.This can lead to improved insulin sensitivity and glucose uptake, which are important for preventing MetS [27].They can also reduce oxidative stress and inflammation by affecting the genes involved in the controlling of the pro-inflammatory nuclear factor kappa-lightchain-enhancer of activated B cells (NF-K) and the anti-inflammatory nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, which in turn can scavenge free radicals, inhibit lipid peroxidation, and downregulate the pro-inflammatory proteins such as toll-like receptor 4 (TLR4) [22], interleukin 1b (IL-1b), and IL-6, and tumor necrosis factor-alpha (TNF-) [48].Lastly, it has been well-identified that polyphenol intake might influence gut microbiota, which through the modulation of inflammation may affect CVD risk biomarkers [49].These findings have important implications for public health sectors to provide evidence-based recommendations for dietary interventions targeting MetS prevention.Accordingly, adherence to a diet with high contents of polyphenol-rich foods such as vegetables, nuts, spices, fruits, virgin olive oil, and seasonings with aromatic plants are recommended as a potential approach to manage MetS.
To the best of our knowledge, this is the first metaanalysis investigating the relationship between dietary intake of polyphenols and their main subclasses to MetS.This study has several strengths, as (i) it comprehensively analyzed various polyphenolic compounds/subclasses with a relatively high sample size for the included studies; (ii) no time or language limitations were considered for the search and no evidence of publication bias was detected; (iii) the reliability of the findings was confirmed by the sensitivity analysis.However, some limitations of the present analysis should be acknowledged.First, there was significant heterogeneity in some analyzes.We applied a random effects model for the analysis to reduce the effect of the observed heterogeneity on the pooled effect sizes.Moreover, a stratified analysis was done to detect the possible sources of the heterogeneity.Subgroup analysis revealed that the identified heterogeneity was explainable by differences in polyphenol subclasses and the definition used for the diagnosis of MetS.Second, analyzed studies were observational, and cause-effect association cannot be fully assessed; therefore, the results might suffer from reverse causation and unmeasured/ residual confounding.Nevertheless, all included publications controlled the results for the potential covariates.Third, exposure assessment was performed using the retrospective dietary questionnaires, which are at risk of recall and measurement biases.Lastly, the small number of the included studies for subclasses of polyphenols did not allow for conducting subgroup analyses for individual subclasses of polyphenols.However, a subgroup analysis was conducted for the overall analysis, which included all polyphenolic compounds.

Conclusions
In summary, the present meta-analysis proposes that polyphenol intake has the potential to reduce the odds of MetS.Plant-based diets with food items rich in polyphenols may represent a potential preventive approach against the rising trend of MetS.Additional studies, particularly clinical trials and prospective studies are required to demonstrate these findings.

Fig.
Fig. 1 Flow diagram of the study

Fig. 2
Fig. 2 Meta-analysis of the association between various polyphenolic compounds and risk of MetS.DL: DerSimonian and Laird random effects model

Fig. 3 Fig. 5
Fig. 3 Meta-analysis of the association between various polyphenol subclasses and risk of MetS.DL: DerSimonian and Laird random effects model

Fig. 4
Fig. 4 Meta-regression analysis according to the age of participants

1
Flow diagram of the study

Table 1
Characteristics of studies

Table 1 (
continued) International Diabetes Federation, ATP III: Adult Treatment Panel III report, AHA/NHLBI: The American Heart Association and the National Heart, Lung, and Blood Institute, FFQ: food frequency questionnaire, BMI: body mass index IDF:

Table 2
Meta-analysis of main results of all polyphenolic compounds and subgroups